The broad goal of this application is to determine which variables influence whether hormone therapy acts as a protectant or a risk factor for cognitive functioning and brain aging. Ovarian hormone loss due to menopause has been linked with cognitive decline and increased risk of Alzheimer's disease. While there is evidence that hormone replacement decreases such effects, recent clinical trials failed to find positive effects, and some found detrimental effects. However, abundant basic science evidence suggests that estrogens exert beneficial effects on cognition and neurobiological variables related to memory. Hence, despite the null and negative findings in some clinical trials, the numerous animal and clinical studies showing positive effects of hormone treatment begs the question of what factors determine whether hormone therapy acts as a protectant or a risk factor for brain functioning and brain aging. We will use the rat model to systematically evaluate variations in current hormone therapies, testing whether they are beneficial or detrimental to cognition, neurotrophins, and markers of synaptic plasticity. Based on prior research, what factors might influence the outcome of estrogen replacement? 1. Dose and type of estrogen. Specific Aim I compares the dose-specific effects of three estrogen preparations: the most commonly used estrogen in animal studies (estradiol), the most commonly used estrogen therapy in the clinic (Premarin, or conjugated equine estrogens), and a promising estrogen therapy that has positive effects on menopausal symptoms (estriol). Neither Premarin nor estriol have been tested for cognitive effects in the rodent. 2. Unopposed vs. opposed estrogen treatment. We recently found that progesterone, given alone, is detrimental to spatial memory, and that tonic estradiol replacement enhances memory and alters neurotrophins in cognitive brain regions in aged rats. When progesterone was added to estradiol treatment, the cognitive and neurotrophin alterations due to estradiol were completely reversed. Specific Aim 2 tests whether the three most common clinically-used progestins alter cognition and the brain when given alone, and counteract estrogen-induced alterations when given as part of combination hormone therapy. Further, we will also test a mechanism of progesterone's effects on cognition. Some metabolites of progesterone have effects on the GABAA receptor. We hypothesize that progesterone is impairing memory by increasing GABAA stimulation, in turn resulting in greater hippocampal inhibition thereby impairing memory. By using GABAA antagonists and agonists as well as metabolites of progesterone that mediate the actions of GAB A on the GABAA receptor, Specific Aim 3 will test whether progesterone's negative effects on cognition, when given alone and concurrently with estradiol, are due to effects mediated by the GABAA system. In each study, rats will be tested on a battery of spatial and non-spatial working and reference memory tests, followed by evaluations of neurotrophin levels and markers of synaptic plasticity in cognitive brain regions. These studies will help elucidate which variations in hormone therapy attenuate or exacerbate age-related changes in cognition and the brain, as well as the mechanism of progesterone's effects when given alone and with estrogen.